tbuckley/cabot-search huggingface dataset:
The fat is in the lysosome: how Mycobacterium tuberculosis tricks macrophages into storing lipids
Authors: Yoann Rombouts, Olivier Neyrolles
Journal: Journal of Clinical Investigation (2023)

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects primarily macrophages, causing them to differentiate into lipid-laden foamy macrophages that are a primary source of tissue destruction in patients with TB. In this issue of the JCI, Bedard et al. demonstrate that 1-tuberculosinyladenosine, a virulence factor produced by M. tuberculosis, caused lysosomal dysfunction associated with lipid storage in the phagolysosome of macrophages in a manner that mimicked lysosomal storage diseases. This work sheds light on how M. tuberculosis manipulates host lipid metabolism for its survival and opens avenues toward host-directed therapy against TB.
Randomized Phase II Cabazitaxel Dose Individualization and Neutropenia Prevention Trial in Patients with Metastatic Castration-Resistant Prostate Cancer
Authors: Aurelius Omlin, Richard Cathomas, Gunhild von Amsberg, Christoph Reuter, Susan Feyerabend, Wolfgang Loidl, Martin Boegemann, Anja Lorch, Axel Heidenreich, Igor Tsaur, Julian Larcher-Senn, Stefan A.J. Buck, Ron H.J. Mathijssen, Ulrich Jaehde, Silke Gillessen, Markus Joerger
Journal: Clinical Cancer Research (2023)

There is ongoing controversy about the recommended dose of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC).This multicenter phase II open-label, randomized, parallel-group study compared 3-weekly cabazitaxel at 25 mg/m2 (conventional arm A) with cabazitaxel therapeutic drug monitoring (experimental arm B) in mCRPC. The primary objective was to improve the clinical feasibility rate (CFR), defined as the absence of grade 4 neutropenia or thrombocytopenia, any thrombocytopenia with bleeding, febrile neutropenia, severe nonhematologic toxicity, withdrawal for cabazitaxel-related toxicity, or death. A total of 60 patients had to be randomized to detect a difference in CFR of 35% (power 80%, two-sided alpha 10%).A total of 40 patients were randomized to arm A and 33 patients to arm B. CFR was 69.4% in arm A and 64.3% in arm B (P = 0.79). Week-12 PSA response was 38.5% in both arms. A radiological response by RECIST v.1.1 was seen in 3 (9.7%) patients in arm A versus 6 (23.1%) patients in arm B (P = 0.28), disease progression was higher in arm A compared with arm B (61.3% vs. 30.8%, P = 0.05). Median progression-free survival was longer in arm B compared with arm A (9.5 vs. 4.4 months; HR = 0.46; P = 0.005). Median overall survival was higher in arm B compared with arm A (16.2 vs. 7.3 months; HR = 0.33; P < 0.0001).Pharmacokinetic-guided dosing of cabazitaxel in patients with mCRPC is feasible and improves clinical outcome due to individual dose escalations in 55% of patients.
3D Biomimetic Models to Reconstitute Tumor Microenvironment In Vitro: Spheroids, Organoids, and Tumor‐on‐a‐Chip
Authors: Wenxiu Li, Zhihang Zhou, Xiaoyu Zhou, Bee Luan Khoo, Renardi Gunawan, Y. Rebecca Chin, Liang Zhang, Changqing Yi, Xinyuan Guan, Mengsu Yang
Journal: Advanced Healthcare Materials (2023)

Abstract Decades of efforts in engineering in vitro cancer models have advanced drug discovery and the insight into cancer biology. However, the establishment of preclinical models that enable fully recapitulating the tumor microenvironment remains challenging owing to its intrinsic complexity. Recent progress in engineering techniques has allowed the development of a new generation of in vitro preclinical models that can recreate complex in vivo tumor microenvironments and accurately predict drug responses, including spheroids, organoids, and tumor‐on‐a‐chip. These biomimetic 3D tumor models are of particular interest as they pave the way for better understanding of cancer biology and accelerating the development of new anticancer therapeutics with reducing animal use. Here, the recent advances in developing these in vitro platforms for cancer modeling and preclinical drug screening, focusing on incorporating hydrogels are reviewed to reconstitute physiologically relevant microenvironments. The combination of spheroids/organoids with microfluidic technologies is also highlighted to better mimic in vivo tumors and discuss the challenges and future directions in the clinical translation of such models for drug screening and personalized medicine.
Nonsuppressible viremia during HIV-1 therapy meets molecular virology
Authors: Ann Emery, Sarah B. Joseph, Ronald Swanstrom
Journal: Journal of Clinical Investigation (2023)

HIV-1 replication can be suppressed with antiretroviral therapy (ART), but individuals who stop taking ART soon become viremic again. Some people experience extended times of detectable viremia despite optimal adherence to ART. In this issue of the JCI, White, Wu, and coauthors elucidate a source of nonsuppressible viremia (NSV) in treatment-adherent patients - clonally expanded T cells harboring HIV-1 proviruses with small deletions or mutations in the 5'-leader, the UTR that includes the major splice donor site of viral RNA. These mutations altered viral RNA-splicing efficiency and RNA dimerization and packaging, yet still allowed production of detectable levels of noninfectious virus particles. These particles lacked the HIV-1 Env surface protein required for cell entry and failed to form the mature capsid cone required for infectivity. These studies improve our understanding of NSV and the regulation of viral functions in the 5'-leader with implications for rationalized care in individuals with NSV.
Glia in FTLD-GRN: from supporting cast to leading role
Authors: Emile S. Pinarbasi, Sami J. Barmada
Journal: Journal of Clinical Investigation (2023)

A subset of the neurodegenerative disease frontotemporal lobar degeneration (FTLD) is caused by mutations in the progranulin (GRN) gene. In this issue of the JCI, Marsan and colleagues demonstrate disease-specific transcriptional profiles in multiple glial cell lineages - astrocytes, microglia, and oligodendroglia - that are highly conserved between patients with FTLD-GRN and the widely used Grn-/- mouse model. Additionally, the authors show that Grn-/- astrocytes fail to adequately maintain synapses in both mouse and human models. This study presents a compelling argument for a central role for glia in neurodegeneration and creates a rich resource for extending mechanistic insight into pathophysiology, identifying potential biomarkers, and developing therapeutic approaches.
Skin diseases and emerging determinants: the need for interactive research
Authors: Nidhi Singh, Tamara Schikowski
Journal: British Journal of Dermatology (2023)

Journal Article Skin diseases and emerging determinants: the need for interactive research Get access Nidhi Singh, Nidhi Singh IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany Search for other works by this author on: Oxford Academic Google Scholar Tamara Schikowski Tamara Schikowski IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany Correspondence: Tamara Schikowski. Email: Tamara.Schikowski@IUF-Duesseldorf.de Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 188, Issue 4, April 2023, Pages 457–458, https://doi.org/10.1093/bjd/ljad008 Published: 14 March 2023 Article history Received: 06 January 2023 Corrected and typeset: 14 March 2023 Published: 14 March 2023
Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study
Authors: Matteo Lazzeroni, Matteo Puntoni, Aliana Guerrieri-Gonzaga, Davide Serrano, Luca Boni, Tania Buttiron Webber, Marianna Fava, Irene M. Briata, Livia Giordano, Maria Digennaro, Laura Cortesi, Fabio Falcini, Patrizia Serra, Franca Avino, Francesco Millo, Katia Cagossi, Elisa Gallerani, Alessia De Simone, Anna Cariello, Giuseppe Aprile, Maria Renne, Bernardo Bonanni, Andrea DeCensi
Journal: Journal of Clinical Oncology (2023)

Five-year data of the phase III trial TAM-01 showed that low-dose tamoxifen at 5 mg once daily administered for 3 years in women with intraepithelial neoplasia (IEN) reduced by 52% the recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), without additional adverse events over placebo. Here, we present the 10-year results.We randomly assigned 500 women with breast IEN (atypical ductal hyperplasia, lobular carcinoma in situ [LCIS], or hormone-sensitive or unknown DCIS) to low-dose tamoxifen or placebo after surgery with or without irradiation. The primary end point was the incidence of invasive breast cancer or DCIS.The TAM-01 population included 500 women (20% atypical ductal hyperplasia, 11% LCIS, and 69% DCIS). The mean (±SD) age at the start of treatment was 54 ± 9 years, and 58% of participants were postmenopausal. After a median follow-up of 9.7 years (IQR, 8.3-10.9 years), 66 breast cancers (15 in situ; 51 invasive) were diagnosed: 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years, 11.3 with tamoxifen v 19.5 with placebo; hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.95; log-rank P = .03). Most recurrences were invasive (77%) and ipsilateral (59%). Regarding contralateral breast cancer incidence, there were six events in the tamoxifen arm and 16 in the placebo arm (HR, 0.36; 95% CI, 0.14 to 0.92; P = .025). The number needed to be treated to prevent one case of breast event with tamoxifen therapy was 22 in 5 years and 14 in 10 years. The benefit was seen across all patient subgroups. There was a significant 50% reduction of recurrence with tamoxifen in the DCIS cohort, which represents 70% of the overall population (HR, 0.50; 95% CI, 0.28 to 0.91; P = .02). No between-group difference in the incidence of serious adverse events was reported during the prolonged follow-up period.Tamoxifen 5 mg once daily for 3 years significantly prevents recurrence from noninvasive breast cancer after 7 years from treatment cessation without long-term adverse events.
Vascular–Parenchymal Cross-Talk Promotes Lung Fibrosis through BMPR2 Signaling
Authors: Toyoshi Yanagihara, Kazuya Tsubouchi, Quan Zhou, Michael Chong, Kohei Otsubo, Takuma Isshiki, Jonas C. Schupp, Seidai Sato, Ciaran Scallan, Chandak Upagupta, Spencer Revill, Anmar Ayoub, Sy Giin Chong, Anna Dvorkin-Gheva, Naftali Kaminski, Jussi Tikkanen, Shaf Keshavjee, Guillaume Paré, Christophe Guignabert, Kjetil Ask, Martin R. J. Kolb
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive lung scarring. IPF-related pulmonary vascular remodeling and pulmonary hypertension (PH) result in a particularly poor prognosis. Objectives: To study the pathogenesis of vascular remodeling in fibrotic lungs and its contribution to progression of fibrosis. Methods: We used an experimental model of lung fibrosis associated with PH by transient overexpression of active TGF-β1 (transforming growth factor-β1). Samples from patients with fibrotic lung diseases were analyzed in depth using immunostaining, gene expression, and gene mutations. Measurements and Main Results: We found a reduction in endothelial cells (ECs) and activation of vascular smooth muscle cells (VSMCs) in fibrotic lungs. Coculturing fibroblasts with VSMCs or ECs from fibrotic lungs induced fibrotic phenotypes in fibroblasts. IPF fibroblasts induced EC death and activation of VSMCs in coculture systems. Decreased concentrations of BMPR2 (bone morphogenic protein receptor 2) and its signaling were observed in ECs and VSMCs from fibrotic lungs in both rats and humans. On fibroblasts treated with media from VSMCs, BMPR2 suppression in VSMCs led to fibrogenic effects. Tacrolimus activated BMPR2 signaling and attenuated fibrosis and PH in rodent lungs. Whole-exome sequencing revealed rare mutations in PH-related genes, including BMPR2, in patients with IPF undergoing transplantation. A unique missense BMPR2 mutation (p.Q721R) was discovered to have dysfunctional effects on BMPR2 signaling. Conclusions: Endothelial dysfunction and vascular remodeling in PH secondary to pulmonary fibrosis enhance fibrogenesis through impaired BMPR2 signaling. Tacrolimus may have value as a treatment of advanced IPF and concomitant PH. Genetic abnormalities may determine the development of PH in advanced IPF.
Evaluating a Comprehensive Model of Euthymia
Authors: Jeffrey R. Vittengl, Robin B. Jarrett, Eunyoe Ro, Lee Anna Clark
Journal: Psychotherapy and Psychosomatics (2023)

Introduction: In research and treatment of mood disorders, “euthymia” traditionally denotes the absence of clinically significant mood disturbance. A newer, expanded definition of euthymia also includes positive affect and psychological well-being. Objective: We aimed to test this comprehensive model of euthymia and estimate the coherence and predictive power of each factor in the model. Methods: Community-dwelling adults (N = 601), including both mental health outpatients and non-patients at high risk for personality pathology, completed a battery of interviews and questionnaires at time 1. Most (n = 497) were reassessed on average 8 months later (time 2). We modeled euthymia using standard mood, personality, and psychosocial functioning assessments rather than measures designed specifically for euthymia. Results: The hypothesized model of euthymia was supported by confirmatory factor analysis: specific measures loaded on three lower order factors (mood disturbance, positive affect, and psychological well-being) that reflected general euthymia at time 1. Each factor (general euthymia plus lower order factors) demonstrated moderately strong concurrent (time 1) and predictive (time 1–2) correlations with outcomes, including employment status, income, mental health treatment consumption, and disability. Compared to positive affect and psychological well-being, mood disturbance had stronger incremental (i.e., nonoverlapping) relations with these outcomes. Conclusions: Support for a comprehensive model of euthymia reinforces efforts to improve assessment and treatment of mood and other disorders. Beyond dampening of psychological distress, euthymia-informed treatment goals encompass full recovery, including enjoyment and meaning in life.
Cognition from the Body-Brain Partnership: Exaptation of Memory
Authors: György Buzsáki, David Tingley
Journal: Annual Review of Neuroscience (2023)

Examination of cognition has historically been approached from language and introspection. However, human language-dependent definitions ignore the evolutionary roots of brain mechanisms and constrain their study in experimental animals. We promote an alternative view, namely that cognition, including memory, can be explained by exaptation and expansion of the circuits and algorithms serving bodily functions. Regulation and protection of metabolic and energetic processes require time-evolving brain computations enabling the organism to prepare for altered future states. Exaptation of such circuits was likely exploited for exploration of the organism's niche. We illustrate that exploration gives rise to a cognitive map, and in turn, environment-disengaged computation allows for mental travel into the past (memory) and the future (planning). Such brain-body interactions not only occur during waking but also persist during sleep. These exaptation steps are illustrated by the dual, endocrine-homeostatic and memory, contributions of the hippocampal system, particularly during hippocampal sharp-wave ripples.
Comment on ‘Prognostic value of neutrophil-to-lymphocyte ratio in colorectal cancer liver metastasis: a meta-analysis of results from multivariate analysis’
Authors: Miaoying Zhao
Journal: International Journal of Surgery (2023)

Outpatient office, YiWu Central Hospital, Zhejiang 322000, China Running Title: neutrophil-to-lymphocyte ratio and colorectal cancer liver metastasis. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: Outpatient office, YiWu Central Hospital, Zhejiang 322000, China. E-mail address: [email protected] (M. Zhao). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/
Society News
Journal: Neuro-Oncology (2023)

Journal Article Society News Get access Neuro-Oncology, Volume 25, Issue 3, March 2023, Page 616, https://doi.org/10.1093/neuonc/noad023 Published: 14 March 2023 Article history Corrected and typeset: 14 March 2023 Published: 14 March 2023
Identification of High-Risk Coronary Lesions by 3-Vessel Optical Coherence Tomography
Authors: Senqing Jiang, Chao Fang, Xueming Xu, Lei Xing, Sibo Sun, Cong Peng, Yanwei Yin, Fangmeng Lei, Yini Wang, Lulu Li, Yuzhu Chen, Xueying Pei, Ruyi Jia, Caiying Tang, Song Li, Shuang Li, Huai Yu, Tao Chen, Jinfeng Tan, Xiaohui Liu, Jingbo Hou, Jiannan Dai, Bo Yu
Journal: Journal of the American College of Cardiology (2023)
Improving health outcomes of people with diabetes: target setting for the WHO Global Diabetes Compact
Authors: Edward W Gregg, James Buckley, Mohammed K Ali, Justine Davies, David Flood, Roopa Mehta, Ben Griffiths, Lee-Ling Lim, Jennifer Manne-Goehler, Jonathan Pearson-Stuttard, Nikhil Tandon, Gojka Roglic, Slim Slama, Jonathan E Shaw, Kokou Agoudavi, Krishna K. Aryal, Rifat Atun, Silver Bahendeka, Brice Wilfried Bicaba, Pascal Bovet, Garry Brian, Albertino Damasceno, Justine I. Davies, Maria Dorobantu, Farshad Farzadfar, David Flood, Pascal Geldsetzer, Mongal Singh Gurung, David Guwatudde, Corine Houehanou, Dismand Houinato, Nahla Hwalla, Lindsay Jaacks, Bahadur Khem Karki, Demetre Labadarios, Nuno Lunet, Jennifer Manne-Goehler, Maja E. Marcus, Joao Martins, Theodory Mary Mayige, Bolormaa Norov, Sahar Saeedi Moghaddam, Sarah Quesnel-Crooks, Abla M. Sibai, Lela Sturua, Michaela Theilmann, Lindiwe Tsabedze, Sebastian Vollmer, Zhaxybay Zhumadilov
Journal: The Lancet (2023)
Diffuse alveolar haemorrhage during pregnancy in systemic lupus erythematosus
Authors: Pradip Dashraath, Claudia R H Tong, May Shuen Tang, Sarah Li, Jeslyn J L Wong, Kay Leong Khoo, Ju Ee Seet, Citra N Z Mattar, Peter P Cheung
Journal: The Lancet Rheumatology (2023)
Machine learning-based automated sponge cytology for screening of oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction: a nationwide, multicohort, prospective study
Authors: Ye Gao, Lei Xin, Han Lin, Bin Yao, Tao Zhang, Ai-Jun Zhou, Shu Huang, Jian-Hua Wang, Ya-Dong Feng, Sheng-Hua Yao, Yan Guo, Tong Dang, Xian-Mei Meng, Zeng-Zhou Yang, Wan-Qi Jia, Hui-Fang Pang, Xiao-Juan Tian, Bin Deng, Jun-Ping Wang, Wen-Chuan Fan, Jun Wang, Li-Hong Shi, Guan-Yu Yang, Chang Sun, Wei Wang, Jun-Cai Zang, Song-Yang Li, Rui-Hua Shi, Zhao-Shen Li, Luo-Wei Wang
Journal: The Lancet. Gastroenterology & hepatology (2023)
International manufacturing and trade in colistin, its implications in colistin resistance and One Health global policies: a microbiological, economic, and anthropological study
Authors: Muhammad Umair, Brekhna Hassan, Refath Farzana, Qasim Ali, Kirsty Sands, Jordan Mathias, Seniyat Afegbua, Mohammad Nazmul Haque, Timothy R Walsh, Mashkoor Mohsin
Journal: The Lancet Microbe (2023)
Enhancement of oligodendrocyte autophagy alleviates white matter injury and cognitive impairment induced by chronic cerebral hypoperfusion in rats
Authors: Huiyang Wang, Yueyang Liu, Zhenkun Guo, Minghui Cui, Peng Pang, Jingyu Yang, Chunfu Wu
Journal: Acta Pharmaceutica Sinica B (2023)

Cognitive impairment caused by chronic cerebral hypoperfusion (CCH) is associated with white matter injury (WMI), possibly through the alteration of autophagy. Here, the autophagy-lysosomal pathway (ALP) dysfunction in white matter (WM) and its relationship with cognitive impairment were investigated in rats subjected to two vessel occlusion (2VO). The results showed that cognitive impairment occurred by the 28th day after 2VO. Injury and autophagy activation of mature oligodendrocytes and neuronal axons sequentially occurred in WM by the 3rd day. By the 14th day, abnormal accumulation of autophagy substrate, lysosomal dysfunction, and the activation of mechanistic target of rapamycin (MTOR) pathway were observed in WM, paralleled with mature oligodendrocyte death. This indicates autophagy activation was followed by ALP dysfunction caused by autophagy inhibition or lysosomal dysfunction. To target the ALP dysfunction, enhanced autophagy by systemic rapamycin treatment or overexpression of Beclin1 (BECN1) in oligodendrocytes reduced mature oligodendrocyte death, and subsequently alleviated the WMI and cognitive impairment after CCH. These results reveal that early autophagy activation was followed by ALP dysfunction in WM after 2VO, which was associated with the aggravation of WMI and cognitive impairment. This study highlights that alleviating ALP dysfunction by enhancing oligodendrocyte autophagy has benefits for cognitive recovery after CCH.
Association of demographic factors and medical school research productivity with dermatology residency tier placement: A national cohort study
Authors: Harrison Zhu, Austin Huang, Kelvin Zhou, Anshul Bhatnagar, Ryan Sorensen, Kathryn Cordova, Gianmarco A. Calderara, Nina Dasari, Randall Parker Kirby, Soo Jung Kim
Journal: Journal of the American Academy of Dermatology (2023)
Role of E2F transcription factor in oral cancer: Recent insight and advancements
Authors: Amal Kassab, Ishita Gupta, Ala-Eddin Al Moustafa
Journal: Seminars in Cancer Biology (2023)

The family of mammalian E2F transcription factors (E2Fs) comprise of 8 members (E2F1-E2F8) classified as activators (E2F1-E2F3) and repressors (E2F4-E2F8) primarily regulating the expression of several genes related to cell proliferation, apoptosis and differentiation, mainly in a cell cycle-dependent manner. E2F activity is frequently controlled via the retinoblastoma protein (pRb), cyclins, p53 and the ubiquitin-proteasome pathway. Additionally, genetic or epigenetic changes result in the deregulation of E2F family genes expression altering S phase entry and apoptosis, an important hallmark for the onset and development of cancer. Although studies reveal E2Fs to be involved in several human malignancies, the mechanisms underlying the role of E2Fs in oral cancer lies nascent and needs further investigations. This review focuses on the role of E2Fs in oral cancer and the etiological factors regulating E2Fs activity, which in turn transcriptionally control the expression of their target genes, thus contributing to cell proliferation, metastasis, and drug/therapy resistance. Further, we will discuss therapeutic strategies for E2Fs, which may prevent oral tumor growth, metastasis, and drug resistance.